Corrochano Silvia, Renna Maurizio, Osborne Georgina, Carter Sarah, Stewart Michelle, May Joel, Bates Gillian P, Brown Steve D M, Rubinsztein David C, Acevedo-Arozena Abraham
MRC Mammalian Genetics Unit, Harwell, Oxfordshire, United Kingdom.
Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Wellcome/MRC Building, Addenbrooke's Hospital, Cambridge, United Kingdom.
PLoS One. 2014 Aug 20;9(8):e105595. doi: 10.1371/journal.pone.0105595. eCollection 2014.
Many of the neurodegenerative diseases that afflict people in later life are associated with the formation of protein aggregates. These so-called "proteinopathies" include Alzheimer's disease (AD) and Huntington's disease (HD). The insulin/insulin-like growth factor signalling (IIS) pathway has been proposed to modulate such diseases in model organisms, as well as the general ageing process. In this pathway, insulin-like growth factor binds to insulin-like growth factor receptors, such as the insulin-like growth factor 1 receptor (IGF-1R). Heterozygous deletion of Igf-1r has been shown to lead to increased lifespan in mice. Reducing the activity of this pathway had benefits in a HD C. elegans model, and some of these may be attributed to the expected inhibition of mTOR activity resulting in an increase in autophagy, which would enhance mutant huntingtin clearance. Thus, we tested if heterozygous deletion of Igf-1r would lead to benefits in HD related phenotypes in the mouse. Surprisingly, reducing Igf-1r levels led to some beneficial effects in HD females, but also led to some detrimental effects in HD males. Interestingly, Igf-1r deficiency had no discernible effects on downstream mTOR signalling in HD mice. These results do not support a broad beneficial effect of diminishing the IIS pathway in HD pathology in a mammalian system.
许多困扰老年人的神经退行性疾病都与蛋白质聚集体的形成有关。这些所谓的“蛋白质病”包括阿尔茨海默病（AD）和亨廷顿舞蹈病（HD）。胰岛素/胰岛素样生长因子信号通路（IIS）已被提出在模式生物中调节此类疾病以及一般衰老过程。在该通路中，胰岛素样生长因子与胰岛素样生长因子受体结合，如胰岛素样生长因子1受体（IGF-1R）。已证明Igf-1r的杂合缺失会导致小鼠寿命延长。降低该通路的活性在HD秀丽隐杆线虫模型中具有益处，其中一些可能归因于预期的mTOR活性抑制导致自噬增加，这将增强突变型亨廷顿蛋白的清除。因此，我们测试了Igf-1r的杂合缺失是否会对小鼠HD相关表型产生益处。令人惊讶的是，降低Igf-1r水平对HD雌性小鼠产生了一些有益影响，但也对HD雄性小鼠产生了一些有害影响。有趣的是，Igf-1r缺乏对HD小鼠的下游mTOR信号没有明显影响。这些结果不支持在哺乳动物系统中减少IIS通路对HD病理学具有广泛有益作用的观点。
